CA2483817C - Novel ligands that are inhibitors of the rar receptors, process for preparing them and use thereof in human medicine and in cosmetics - Google Patents

Novel ligands that are inhibitors of the rar receptors, process for preparing them and use thereof in human medicine and in cosmetics Download PDF

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CA2483817C
CA2483817C CA2483817A CA2483817A CA2483817C CA 2483817 C CA2483817 C CA 2483817C CA 2483817 A CA2483817 A CA 2483817A CA 2483817 A CA2483817 A CA 2483817A CA 2483817 C CA2483817 C CA 2483817C
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tetrahydro
tetramethyl
naphthyl
benzoic acid
hydroxy
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CA2483817A1 (en
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Thibaud Biadatti
Pascal Collette
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Galderma Research and Development SNC
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    • C07C65/17—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
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Abstract

The invention relates to novel biaryl compounds corresponding to the general formula (I) below: and to the method for preparing them, and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.

Description

Novel ligands that are inhibitors of the RAR receptors, process for preparing them and use thereof in human medicine and in cosmetics The invention relates to biaryl compounds, as novel and useful industrial products. The invention also relates to the process for preparing them and to their use in pharmaceutical compositions for use in human or veterinary medicine, or in cosmetic compositions.

Compounds with activity of retinoid type (vitamin A and its derivatives) are widely described in the literature as having activity in cell differentiation and proliferation processes. These properties give this class of compounds great potential in the treatment or prevention of numerous pathologies, and more particularly in dermatology and cancer. Many biological effects of retinoids are mediated by modulating the nuclear retinoic acid receptors (RAR), which are factors for transcribing ligand-dependent genes.

RAR receptors activate transcription by binding to DNA sequence elements, known as the RAR
Element (RARE) response elements, in the form of a heterodimer with the retinoid x receptors (known as RXRs).

Three subtypes of human RARs have been identified and described: RAROG, RAR(3 and RARy.

The prior art contains a large number of chemical compounds with inhibitory activity on receptors of RAR type. Among the prior art documents SUBSTITUTE SHEET (RULE 26) that may be mentioned more particularly are patent EP 0 986 537 which describes heteroethynylenated compounds, patent US'6 103 762 describing biaromatic compounds in which the aromatic nuclei are linked to a propynylene or allenylene divalent radical, patent US 6 150 413, which describes triaromatic compounds, patent US 5 723 499 which describes polycyclic aromatic compounds, and patent US 6 214 878 which describes stilbene compounds. Patent US 6 218 128 itself 10, describes a family of bicyclic or tricyclic molecules.
The Applicant has invented novel biaryl compounds that inhibit the retinoic acid receptors.

Thus, the present invention relates to biaryl compounds corresponding to the general formula below:

R3 (I) in which:

- R1 represents a radical of formulae (a) to (c) below:

(a) (b) (C) R5 and R6 having the meanings given below, each of the radicals R2 and R3, which may be identical or different, represent a hydrogen atom, a linear or branched alkyl radical of 1to 6 carbon atoms, a radical -OR7 or a radical -NR8R9, or R2 and R3, taken together, form a 6-membered ring optionally substituted with linear or branched alkyl radicals of 1 to 3 carbons, R7, R8 and R9 having the meanings given below, R4 represents an aryl radical or a heterocyclic radical, X represents -CR10R11, -C=O or -C=N-OR12, R10, R11 and R12 having the meanings given below, R5 represents a hydroxyl, alkoxy, monoalkylamino or dialkylamino radical, or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, - R6 represents a radical chosen from:
R14 0,R13 R13 O N
R13 and R14 having the meanings given below, R7 represents a hydrogen atom, an alkyl containing from 1 to 6 carbon atoms, or a benzyl radical optionally substituted with a linear or branched alkyl containing from 1 to 6 carbon atoms, a halogen or a dialkylamino or alkoxy radical, R8 and R9, which may be identical or different, represent a hydrogen atom,. a linear or branched alkyl radical containing from i to 6 carbon atoms, or a benzyl radical, R10 represents a hydrogen atom or an -OH
radical, R11 and R12, which may be identical or different, represent--a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, R13 represents a hydroxyl, alkoxy, monoalkylamino or dialkylamino group, - R14 represents a hydrogen atom, a hydroxyl radical or an amino radical, and the optical isomers, the salts obtained with a salt or a pharmaceutically acceptable base, and also the mixtures of the said compounds of formula (I).

When the compounds according to the invention are in the form of a salt, it is preferably a salt of an alkali metal or alkaline-earth metal, or alternatively a zinc salt or salts of an organic amine.

4a The invention provides a biaryl compound having the structural formula:

H
H H

HNC I
R

double or 14 H3C CH3 H R10 R11 triple bond R14 wherein:
R10 is a hydrogen atom or an -OH radical R1 1 is a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms or R10 and R11 together represent a CO radical;

R13 is a hydroxyl, alkoxy, monoalkylamino or dialkylamino group;
R14 is a hydrogen atom, a hydroxyl group or amino group; and 20 the para-position of the benzene ring bonded to the 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene is optionally substituted with a linear or branched alkyl radical having from 1 to 6 carbon atoms, an alkoxy radical, a monoalkylamino radical, a dialkylamino radical or a halogen atom, a salt or an optical or geometrical isomer thereof.
The invention also provides a salt of the biaryl compound as defined above.
The invention also provides an alkali or alkaline-earth or zinc or organic amine salt of the biaryl compound as defined above.

4b The invention also provides a pharmaceutical composition comprising at least one biaryl compound as defined above, or a salt or an optical or geometrical isomer thereof, formulated into a physiologically acceptable medium therefor.
The invention also provides a cosmetic composition comprising at least one biaryl compound as defined above, or a salt or an optical or geometrical isomer thereof, formulated into a cosmetically acceptable medium therefor.
The invention also provides a composition comprising a mixture of compounds a defined above.
According to the present invention:

the expression "alkyl radical containing from 1 to 6 carbon atoms" preferably means methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl radicals.

The term."halogen atom" preferably means a 5 fluorine, chlorine or bromine atom.

.The term "alkoxy radical" means an oxygen atom substituted with a linear or branched alkyl radical containing from l'to 6 carbon atoms, and preferably a methoxy-, ethoxy, propyloxy, isopropoxy, butoxy, tert-butoxy, pentoxy.or.hexyloxy radical.
The term "aryl radical" means a phenyl radical optionally substituted with one or more linear or branched alkyl radicals containing from 1 to 6 carbon atoms, an alkoxy radical, a monoalkylamino radical, a dialkylamino radical or a halogen.

The term "monoalkylamino.radical" means an amino radical substituted with a linear or branched alkyl radical containing from 1 to 6 carbon atoms.

The term "dialkylamino radical" means an amino radical disubstituted with linear or branched alkyl radicals, which may be identical or different, containing from 1 to 6 carbon atoms.

The term "heterocyclic radical" means a carbon-based ring of 5 to 8 carbon atoms interrupted with 1 or 2 hetero atoms chosen from sulphur, nitrogen and oxygen, and preferably a pyridine, morpholine, piperidine, piperazine or tetrahydropyridine n-substituted with an alkyl or with an alkylcarbamate in which the alkyl group contains from 1 to 4 carbon atoms.

Among the compounds corresponding to the general, formula (I) above, mention may be made of the following, alone or as a mixture:
4-[3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-hydroxy-1-propynyl]benzoic acid 4-[(E)-3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[(E)-3-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[(E)-3-(5-tert-Butyl-6-isobutoky-4'-methyl-3=
biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[3-Hydroxy-3-(5,5,8,8-t,etramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 4-{3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}benzoic acid 4-{(E)-3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopr'openyl)benzoic acid 4-[(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl]benzoic acid 4-[(E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl]benzoic acid 4-{(E)-3-[4-('4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid 4-{(E)-3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid 4-{3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6',7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}-2-hydroxybenzoic acid 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic 15= acid 2-Hydroxy-4-(3-hydroxy-3-(5,5,8,8-tetramethyl-4-p tolyl-5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl)benzoic acid 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 4-{3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}benzoic acid 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid 4-{(E)-3-.[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl)-2-hydroxybenzoic acid 4-{3-['4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}-2-hydroxybenzoic acid 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 4-{3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl)benzoic acid 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid.

4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7, 8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid 4-{3-.[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-.
5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}-2-hydroxybenzoic acid 4-((E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl)benzoic acid 4-{3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}benzoic acid 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid 4-{3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}-2-hydroxybenzoic acid 4-{(E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-pyrid-4-yl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 4-{ (E) -3-Oxo-3- (5, 5, 8, 8-tetramethyl-4-pyrid-4-yl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-pyrid-4-yl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-pyrid-4-yl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-pyrid 4-yl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[3-hydroxy-3-.(5,5,8,8-tetramethyl-4-pyrid-5 4-yl-5,6,7,8-tetrahydro-2-naphthyl)-1-propyny,l]benzoic acid 4-{(E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 10 4-[(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5,-6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 4-{(E)-3-Hydroxy-3-[5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 4-[(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-isopropyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 4-{(E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid .
4-[(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,.8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4-pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 2-Hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-4-(1-carboxyethyl-1,2,3,6-tetrahydro-4=pyridyl)-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid 4-{(E)-3-Hydroxy-3-[4-(4-isopropyl-1-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 4-{(E)-3-[4-(4-Isopropyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 4-{3-Hydroxy-3-[4-(4-isopropyl-l-piperazinyl)-5,5,8,8-tetramethyl'5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl}benzoic acid 2-Hydroxy-4-{(E)-3-hydroxy-3-[4-(4-isopropyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 2-Hydroxy-4-{(E)-3-[4-(4-isopropyl-l-piperazinyl)-5,5,8;8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 2-Hydroxy-4-{3--hydroxy-3-[4-(4-isopropyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl}benzoic acid 4-{(E)-3-Hydroxy-3-[4-(4-carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 4-{(E)-3-[4-(4-Carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 4-{3-Hydroxy-3-[4-(4-carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1--propynyl}benzoic acid 2-Hydroxy-4-{(E)-3-hydroxy-3-[4-(4=carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 2-Hydroxy-4-{(E)-3-[4-(4-carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 2-Hydroxy-4-{3-hydroxy-3-[4-(4-carboxyethyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl}benzoic acid 4-{(E)-3-Hydroxy-3-[4-(4-methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 4-{(E)-3-[4-(4-Methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl].-3-oxopropenyl}benzoic acid 4-{3-Hydroxy-3-[4-(4-methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl}benzoic acid 2-Hydroxy-4-{(E)-3-hydroxy-3-[4-(4-methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]propenyl}benzoic acid 2-Hydroxy-4-{(E)-3-[4-(4-methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,.7, 8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid 2-Hydroxy-4-{3-hydroxy-3-[4-(4-methyl-l-piperazinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1-propynyl}benzoic acid 6-[1-(5,5,8,8-Tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)methanoyl]naphthalene-2-carboxylic acid 6-[1-Hydroxy-l-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)methyl]naphthalene-2-carboxylic acid 6-{l-[5,5,8,8-Tetramethyl-4-(4-methyl-l-piperazinyl)-5,6,7,8-tetrahydro-2-naphthyl]methanoyl}naphthalene-2-carboxylic acid 6-{1-Hydroxy-l-[5,5,8,8-tetramethyl-4-(4-methyl-l-piperazinyl)-5,6,7,8-tetrahydro-2-.
naphthyl methyl}naphthalene-2-carboxylic acid 4-[(E)-3-(4-Benzyloxy-3-tert-butyl-5-piperid-l-ylphenyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(4-Benzyloxy-3-tert-butyl-5-piperid-l-ylphenyl)-3-oxopropenyl benzoic acid 4-[3-(4-Benzyloxy-3-tert-butyl-5-piperid-1-ylphenyl)-3-hydroxy-l-propynyl]benzoic acid 4-{(E)-3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-oxopropenyl}benzoic acid 4-{3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxy-l-propynyl}benzoic acid 4-{(E)-3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl}-3-hydroxypropenyl)-2-hydroxybenzoic 5 acid 4-{(E)-3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-oxopropenyl}.-2-hydroxybenzoic acid 4-{3-[4-Benzyloxy-3-tert-butyl-5-(4-methyl-l-10. piperazinyl)phenyl]-3-hydroxy-l-propynyl}-2-hydroxybenzoic acid 4-{(E)-3-[4-Benzylamino-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl}-3-oxopropenyl}benzoic acid .4'-{ ('E) -3- [3-tert-Butyl-4-isobutylamino-5- (4-methyl-l-15 piperazinyl)phenyl}-3-oxopropenyl}benzoic acid 4-{(E)-3-[4-(Benzylmethylamino)-3-tert-butyl-5-(4-methyl-1-piperazinyl)phenyl}-3-oxopropenyl}benzoic acid 4-{(E)-3-[3-(5-tert-Butyl)-4-(iso)Dutylmethylamino)-5-(4-methyl-l-piperazinyl)phenyl}-3-oxopropenyl}benzoic acid 4-{(B)-3-[4-Benzylamino-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[4-(Benzylmethylamino)-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[3-tert-Butyl-4-isobutylamino-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[3-tert-Butyl-4-(isobutylmethylamino)-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxypropenyl}benzoic acid 4-{3-[4-Benzylamino-3-tert-butyl-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxy-l-propynyl}benzoic acid 4-{3-[4-(Benzylmethylamino)-3-tert-butyl-5-(4-methyl-l piperazinyl)phenyl]-3-hydroxy-l-propynyl}benzoic acid 4-{3-[3-tert-Butyl-4-isobutylamino-5-(4-methyl-l-piperazinyl)phenyl]-3-hydroxy-l-propynyl}benzoic acid 4-{3-[3-tert-Butyl-4-(isobutylmethylamino)-5-(4-methyl-1-piperazinyl)phenyl]-3-hydroxy-l-propynyl}benzoic acid 4-[(E)-3-(6-Benzylamino-5-tert-butyl-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-{(E)-3-[6-(Benzylmethylamino)-5-tert-butyl-4'-methyl-3-biphenylyl]-3-oxopropenyl}benzoic acid 4-[(E)-3-(5-tert-Butyl-6-isobutylamino-4'-methyl-3-biphenylyl]-3-oxopropenyl]benzoic acid 4-{(E)-3-[5-tert-Butyl-6-(isobutylmethylamino)-4'-methyl-3-biphenylyl]-3-oxopropenyl}benzoic acid 4-[(E)-3-(6-Benzylamino-5-tert-butyl-4.'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-{(E)-3-[6-Benzylmethylamino)-5-tert-butyl-4'-methyl-3-biphenylyl]-3-hydroxypropenyl}benzoic acid 4-[(E)-3-(5-.tert-Butyl-6-isobutylamino-4'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-{(E)-3-(5-tert-Butyl-6-(isobutylmethylamino)-4'-methyl-3-biphenylyl]-3-hydroxypropenyl}benzoic acid 4-[3-(6-Benzylamino-5-tert-butyl-4'-methyl-3-biphenylyl)-3-hydroxy-1-propynyl]benzoic acid 4-{3-[(6-Benzylmethylamino)-5-tert-butyl-4'-methyl-3-biphenylyl]-3-hydroxy-l-propynyl}benzoic acid 4-[3-(5-tert-Butyl-6=isobutylamino-4'-methyl-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 4-{3`-[5-tert-Butyl-6-(isobutylmethylamino)-4'-methyl-3-biphenylyl]-3-hydroxy-l-propynyl}benzoic acid 4-[(E)-3-(6-Dimethylarnino-5-tert-butylmethyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6-Dimethylamino-5-tert-butylmethyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[(E)-3-(6-Dimethylamino-5-tert-butylmethyl-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 4-[(E)-3-(6-Benzylamino-5,4'-di-tert-butyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-{(E)-3-[6-(Benzylmethylamino)-5,4'-di-tert-butyl-3-biphenylyl)-3-oxopropenyl}benzoic acid 4-[(E)-3-(5,4'-di-tert-Butyl-6-isobutylamino-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-{(E)-3-(5,4'-di-tert-Butyl-6-(isobutylmethylamino)-3-biphenylyl]-3-oxopropenyl)benzoic acid 4-[(E)-3-(6-Benzylamino-5,4'-di-tert-butyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-{(E)-3-[6-Benzylmethylamino)-5,4'-di-tert-butyl-3-biphenylyl]-3-hydroxypropenyl}benzoic acid 4-[(E)-3-[5-tert-Butyl-6-isobutylamino-4'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-{(E)-3-[5-tert-Butyl-6-(isobutylmethylamino)-4'-methyl-3-biphenylyl]-3-hydroxypropenyl}benzoic acid 5' 4-[3-(6-Benzylamino-5,4'-di-tert-butyl-3-biphenylyl)-3-hydroxy-l-propynyl benzoic acid 4-{3-[6-(Benzylmethylamino)-5,4'-di-tert-butyl-3-biphenylyl]-3-hydroxy-l-propynyl}benzoic acid 4-[3-(5,4'-di-tert-Butyl-6-isobutylamino-3-biphenylyl)-3-hydroxy-l-propynyl}benzoic acid 4-{3-[5,4'-di-tert-Butyl-6-(isobutylmethylamino)-3-biphenylyl]-3-hydroxy-l-propynyl}benzoic acid 4-{(E)-3-[6-Dimethylamino-5,4'-di-tert-butyl-3-biphenylyl]-3-hydroxypropenyl}benzoic acid 4-{(E)-3-[6-Dimethylamino-5,4'-di-tert-butyl-3-biphenylyl]-3-oxopropenyl}benzoic acid 4-{3-[6-Dimethylamino-5,4'-di-tert-butyl-3-biphenylyl]-3-hydroxy-l-propynyl}benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-dimethylamino-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-dimethylamino-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-(6,4'-di-tert-Butyl-5-dimethylamino-3-biphenylyl)-3-hydroxy-l-propynyl] benzoic acid 4-[(E)-3-(6-tert-Butyl-5-dimethylamino-4'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6-tert-Butyl-5-dimethylamino-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-(6-tert-Butyl-5-dimethylamino-4'-methyl-3 biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-isobutoxy-3-biphenylyl)=
3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-isobutoxy-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-(6,4'-di-tert-Butyl-5-isobutoxy-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 4-[(E)-3-(6-tert-Butyl-5-isobutoxy-4'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6-tert-Butyl-5-isobutoxy-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-,(6-tert-Butyl-5-isobutoxy-4'-methyl-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-benzyloxy-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-[(E)-3-(6,4'-di-tert-Butyl-5-benzyloxy-'3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-(6,4'-di-tert-Butyl-5-benzyloxy-3-biphenylyl)-3-hydroxy-1-propynyl]benzoic acid 4-[(E)-3-(6-tert-Butyl-5-benzyloxy-4'-methyl-3-biphenylyl)-3-hydroxypropenyl]benzoic acid 4-((E)-3-(6-tent-Butyl-5-benzyloxy-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 4-[3-(6-tert-Butyl-5-benzyloxy-4'-methyl-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid 6-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]nicotinc acid 5 6-{3-[4-(4=tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}nicotinic acid 6-[3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-hydroxy-l-propynyl] nicotinic acid 10 6-[3-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-hydroxy-1-propynyl]nicotinic acid 6-[3-(6--Benzyloxy-5,4'-di-tert-butyl-3-biphenylyl)-3-hydroxy-l-propynyl] nicotinic acid 6-[1-Hydroxyimino-1-(5,5,8,8-tetramethyl-4-p-tolyl-15 5,6,7,8-tetrahydro-2-naphthyl)methyl]-2-naphthalenecarboxylic acid 6-[1-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-1-hydroxyiminomethyl}-2-naphthalenecarboxylic acid 20 6-{l-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-1-hydroxyiminomethyl]naphthalenecarboxylic acid or 6-[1-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-1-hydroxyiminomethyl]naphthalenecarboxylic acid.

According to the present invention, the compounds of formula (I) that are more particularly preferred are those for which:.

- R1 represents (a) or (b), and - X represents a radical CR10R11.

A subject of the present invention is also processes for preparing the compounds of formula (I), in particular according to the reaction schemes given in Figure 1.

A general description of the preparation of the compounds of general formulae 6 to 11 is given below.

Compound.4, in the case where R = OR', may be obtained from compound 1 when R2 = OR2' by ortho-iodination and O-alkylation (X = I), from compound 2 when R2 = NR'R" by ortho-iodination (X = I), and -from 3 by conversion of the bromide of 3 into acid or aldehyde after lithiation with butyllithium followed by formylation and formation of the trifluoromethanesulphonyl on the phenol function of the corresponding ester or aldehyde (.X = OTf).

. In the case where R = Br, 4 is obtained from 3 by O-alkylation or double N-alkylation. The intermediate 5 is prepared, for example, from the iodide function of compound 4 (X = I) or a trifluoromethanesulphonyl function of 4 (X = OTf) by a Suzuki, Stille or Buchwald coupling, respectively, with stannic derivatives or aromatic boronic'acids, catalysed with a transition metal complex, for example tetrakis(triphenylphosphinepalladium).
The compounds 5 for which R = COOR' may be converted into acids by saponification, and then. into methyl ketones by reaction with methyllithium: the, compound 5 in which R = COMe are thus obtained.

When the compounds of general structure 5 are obtained, compounds 6-11 are obtained in the following manner:

The compounds 6 may be obtained by formation of the acids corresponding to the esters 5, followed by conversion of these acids into the acid chlorides thereof, for example by reaction with thionyl chloride.
These acid chlorides may then be coupled with organometallic derivatives of naphthylzinc type, or with naphthoic boronic acids, in the presence of catalysts based on transition metals, for example tetrakis(triphenylphosphinepalladium). The precursors of the compounds of general structure 6 are generally obtained in the form of esters: the acids of structure 6 may be obtained by saponification, for example by reaction with sodium-hydroxide.

The compounds 7 may be prepared by forming a chalcone bond by reacting the methyl ketone of 7 with a corresponding aromatic aldehyde in the presence of potassium hydroxide.

The compounds of general structure 8 may be prepared from the aldehyde 7 by creating a propargyl alcohol function by adding a propargyl anion, for example by reaction with ethynylmagnesium bromide, followed by Sonogashira coupling with an aromatic halide such as, for example, 4-iodobenzoic.acid in the presence of copper salts and a catalyst based on a transition metal complex such as, for example, tetrakis (triphenylphosphinepalladium).
The compounds of general structure 9 may be obtained from the compounds of structure 6, for example after reduction or alkylation of the carbonyl function (R3,R4 = OH, H or alkyl, respectively), or alternatively by reduction followed by a dehydroxylation (R3,R4 = H, H), or acetalization of the carbonyl function (R3,R4 = OR, OR), or formation of an oxime on the carbonyl function of 6 by reaction with a corresponding alkoxylamine or hydroxyl.

The compounds of general structure 10 may be obtained from the compounds of structure 7, for example after reduction or alkylation of the carbonyl function (R3, R4 = OH, H or alkyl, respectively) ,, for example reaction with sodium borohydride or an alkylmagnesium halide.

The compounds of general structure 11 may be prepared from the compounds of structure 8, by oxidation of the benzyl alcohol to a ketone (R3, R4 = C=O), for example after reaction with manganese oxide, or oxidation followed by formation of an oxime on the carbonyl function of 8 by reaction with a corresponding alkoxylamine or hydroxyl (R3, R4 = C=N-OR), or dehydroxylation of the benzyl alcohol function (R3, R4 = H,H), for example by reaction with triethylsilane in the presence of boron trifluoride, or by oxidation and formation of an acetal (R3, R4 = OAlk, OAlk), or by oxidation and alkylation of the carbonyl function (R3, R4 = Alkyl, OH), for example by addition of an alkylmagnesium halide, or by 0-alkylation of the alcohol function of 8 (R3, R4 = OAlk,. H) .

The compounds according to the invention have inhibitory properties on RAR-type receptors. This RAR-receptor inhibitory activity is measured in a test of transactivation by means of the dissociation constant Kdapp (apparent) and the IC50 (concentration that inhibits 50% of the reference agonist activity).
According to the invention, the expression "inhibitor of RAR-type receptors" means any compound which, for at least one. of the RAR subtypes, has a dissociation constant Kdapp of less than or equal to 1 pm, and an IC50 value _< 100 nM, in a transactivation test as described in Example 10.

The preferred compounds of the present invention have, for at least one of the RAR subtypes, a dissociation constant Kdapp of less than or equal to 500 nM and advantageously less than or equal to 100 nM.

A subject of the present invention is also the compounds of formula (I) as described above, as medicinal products.

The compounds according to the invention are 5 particularly suitable in the following fields of treatment:

1) for treating dermatological complaints associated with a keratinization disorder relating to cell differentiation and proliferation, especially for 10 treating common acne, comedones, polymorphs, acne rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acnes such as solar acne, medication-related acne or occupational acne;

2) . for treating other types of keratinization 15 disorders, especially ichthyosis, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leucoplakia and leucoplakiform conditions, and cutaneous or mucous (buccal) lichen;

3) for treating other dermatological complaints with 20 an inflammatory immunoallergic component, with or without cell proliferation disorder, and especially all forms of psoriasis, whether cutaneous, mucous or ungual, and even psoriatic rheumatism, or cutaneous atopy, such as eczema, or respiratory atopy, or 25 alternatively gingival hypertrophy;

4) for treating all dermal or epidermal proliferations, whether benign or malignant, and whether of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, T lymphoma, and proliferations that may be induced by ultraviolet radiation, especially in the case of basocellular and spinocellular epithelioma, and also any cutaneous precancerous lesion such as keratoacanthomas;

5) for treating other dermatological disorders such as immune dermatoses, such as lupus erythematosus, immune bullous diseases and collagen diseases, such as scleroderma;

6) in the treatment of dermatological or general complaints with an immunological component;

7) for treating certain opthalmological disorders, especially corneopathies, 8) for preventing or curing the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atropy, 9) in the treatment of any cutaneous or general complaint of viral origin, 10) in the treatment of skin disorders caused by exposure to UV radiation, and also for repairing or combating ageing of the skin, whether photoinduced.or chronological ageing, or for reducing pigmentations and actinic keratosis, or any pathology associated with chronological or actinic ageing, such as xerosis;
11) for combating sebaceous function disorders, such as the hyperseborrhoea of acne or simple seborrhoea;
12) for preventing or treating cicatrization disorders, or for preventing or repairing stretch marks, or alternatively for promoting cicatrization, 13) in the treatment of pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or, vitiligo;

14) in the treatment of lipid metabolism complaints, such as obesity, hyperlipidaemia, or non-insulin-dependent diabetes;

15) in the treatment of inflammatory complaints such as arthritis;

16) in the treatment or prevention of cancerous or precancerous conditions;

17) in the prevention or treatment of alopecia of various origins, especially alopecia caused by chemotherapy or radiation;

18) in the treatment of disorders of the immune system, such as asthma, type I sugar diabetes, multiple sclerosis or other selective dysfunctions of the immune system; and 19) in the treatment of complaints of the cardiovascular system, such as arteriosclerosis or hypertension.

A subject of the present invention is also a pharmaceutical composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.

A subject of the present invention is also a novel medicinal composition intended especially for treating the abovementioned complaints, which is characterized iii that it'comprises, in a pharmaceutically acceptable support that is compatible with the mode of administration selected for this composition, at least one compound of formula (I), an optical isomer thereof or a salt thereof.

The composition according to the invention may be administered enterally, parenterally, topically or ocularly. The pharmaceutical composition is preferably packaged in a form that is suitable for topical application.

Via the enteral route, the composition may be in the form of tablets, gel capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid or polymer vesicles allowing a controlled release. Via the parenteral route, the composition may be in the form of solutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight, in 1 to 3 dosage intakes.
The compounds are used systemically, at a concentration generally of between 0.001% and 10% by weight and preferably between 0.01% and 1% by weight relative to the weight of the composition.

Via the topical route, the pharmaceutical composition according to the invention is more particularly intended for treating the skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks, pomades, powders, impregnated pads, syndets, solutions, gels, sprays, mousses, suspensions, sticks,.
shampoos or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or of lipid or polymer vesicles or gelled or polymer patches allowing a controlled release.

The compounds are used topically at a concentration generally of between 0.001% and 10% by weight and preferably between'0.01% and 1% by weight, relative to the total weight of the composition.

The compounds of formula (I) according to the invention also find an application in cosmetics, in particular in body and hair hygiene and especially for, treating acne-prone skin, for promoting regrowth of the hair or for limiting hair loss, for combating the greasy appearance of the skin or the hair, in protection against the harmful aspects of sunlight or in the treatment of physiologically dry skin, and for preventing and/or combating photoinduced or chronological ageing.

A subject of the invention is thus also a composition comprising, in a cosmetically acceptable 5 support, at least one of the compounds of formula (I).

A subject of the invention is also the cosmetic use of ,a composition comprising at least one compound of formula (I) for preventing and/or treating the signs of ageing and/or dry skin.

10. A subject of the invention is also the cosmetic use of a composition comprising at least one compound of formula (I) for body or hair hygiene.

The cosmetic composition according to the invention containing, in a cosmetically acceptable 15 support, at least one compound of formula (I) or an optical or.geometrical isomer thereof or a salt thereof, may be especially in the form of a cream, a milk, a gel, suspensions of microspheres or nanospheres or lipid or polymer vesicles, impregnated pads, 20 solutions, sprays, mousses, sticks, soaps, shampoos or washing bases.

The concentration of compound of formula (I) in the cosmetic composition is preferably between 0.001% and 3% by weight relative to the total weight of 25 the composition.

The pharmaceutical and cosmetic compositions as described above may also contain inert additives, or even pharmacodynamically active additives as regards the pharmaceutical compositions, or combinations of these additives, and especially:

- wetting agents;

- flavour enhancers;

- preserving agents such as para-hydroxybenzoic acid esters;

- stabilizers;

- moisture regulators;
- pH regulators;

- osmotic pressure modifiers;
- emulsifiers;

- UV-A and W-B screening agents;

- antioxidants such as a-tocopherol, butylhydroxyanisole, butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal-chelating agents;

- depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid;

- emollients;

- moisturizers, for instance glycerol, PEG 400, thiamorpholinone and its derivatives or urea;
- antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, salts thereof or derivatives thereof, or benzoyl peroxide;.

- antibiotics, for instance erythromycin and its ,esters, neomycin, clindamycin and its esters, and tetracyclines;

- antifungal agents such as ketoconazole or poly-4,5-methylene-3-isothiazolidones;

- agents for promoting regrowth of the hair, for instance Minoxidil (2,4-diamino-6-piperi.dinopyrimidine 3-oxide) and its derivatives,.
Diazoxide (7-chloro 3-methyl-l,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4 diphenylimidazolidine-2,4-dione);
- non-steroidal anti-inflammatory agents;
- carotenoids and especially J3-carotene;

- anti-psoriatic agents such as anthralin and its derivatives;

- eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-.
triynoic acid, and esters and amides thereof;

- retinoids, i.e. natural or synthetic RAR or RXR
receptor ligands;

- corticosteroids or oestrogens;

- a-hydroxy acids and a-keto acids or derivatives thereof, such as lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid, and also salts, amides or esters thereof, or (3-hydroxy acids or derivatives thereof, such as salicylic acid and its salts, amides or esters;

- ion-channel blockers such as potassium-channel blockers;

- or alternatively, more particularly for pharmaceutical compositions, in combination with medicinal products-known to interfere with the-immune system (for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, etc.).

Needless to say, a person skilled in the art will take care to select the optional compound(s) to be added to`these compositions such that the advantageous properties intrinsically attached to the present invention are not, or are not substantially, adversely, affected by the envisaged addition.

Examples of the production of active compounds of formula (.I) according to the invention, biological activity results and also various concrete formulations based on such compounds, will now be given, for illustrative purposes and with no limiting nature.

EXAMPLE 1 -- 4-[3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-hydroxy-l-propynyl]benzoic acid a. - 3-tert-Butyl-4-hydroxy-5-iodobenzoic acid 20 g (103 mmol) of 3-tert-butyl-4-hydroxybenzoic acid are dissolved in 400 mL of methanol. 4.12 g (103 mmol) of sodium hydroxide and 15.4 g (103 mmol) of sodium iodide are added. The reaction medium is cooled to 0 C, and 234 g (113 mmol) of 3.6% sodium hypochlorite are added slowly. The medium is stirred at 0 C for 2 hours and is then treated with saturated sodium thiosulphate solution.

The aqueous phase is acidified and 'extracted with ethyl ether. A pale yellow solid is obtained (m = 24.7 g;
yield = 75%; m.p. = 178 C).

b. Methyl 3-tert-butyl-4-hydroxy-5-iodobenzoate 24.7 g (77 mmol) of 3-tert-Butyl-4-hydroxy-5-iodobenzoic acid are dissolved in 500 mL of methanol and 50 mL of THF..,5 mL of concentrated sulphuric acid are added and the reaction medium is refluxed for 18 hours. The reaction medium is concentrated under reduced pressure and then diluted in a dichloromethane/water mixture. The organic phase is washed with water and then concentrated under reduced pressure. A yellow solid is obtained (m = 24.1 g;
yield = 94%; m.p. = 67 C).

c. Methyl 4-benzyloxy-3-tert-butyl-5-iodobenzoate 24.1 g (72 mmol) of methyl 3-tert-butyl-4-hydroxy-5-iodobenzoate are dissolved in 200 mL of dimethylformamide. 3.47 g (86 mmol) of 60% sodium hydride are added slowly and the reaction medium is stirred for 1 hour. 9.4 mL (79 mmol) of benzyl bromide are then added and the medium is stirred at room temperature for 2 hours, and is then hydrolysed and extracted with ethyl ether. The organic phase is washed 3 times with water and then concentrated under reduced pressure. The residue is purified by chromatography (eluent: 98 heptane / 2 ethyl acetate). A yellow oil is obtained (m = 24.3 g; yield = 80%).5 d. Methyl 6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarboxylate 12 g (28 mmol) of methyl 4-benzyloxy-3-tert-butyl-5-iodobenzoate are dissolved with-5.8 g (42 mmol) of 4-methylbenzeneboronic acid and 12.7 g (84 mmol) of 10 caesium fluoride in 400 mL of dioxane. The reaction medium is degassed with a flow of nitrogen for 15 minutes, and 1.7 g (1.4 mmol) of tetrakis(triphenylphosphine)palladium are then added.
The reaction medium is refluxed for 4 hours and then 15 cooled and hydrolysed. After extraction with ethyl acetate, the organic phase is filtered and concentrated.,The residue is purified by chromatography (eluent: 98 heptane / 2 ethyl acetate): a colourless oil is obtained (m = 9 g, yield = 830).

20 e. 6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarbaldehyde 1 g (2.6 mmol) of methyl 6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarboxylate is dissolved in mL of anhydrous ethyl ether, and the medium is 25 cooled to 0 C. 130 mg (3.3 mmol) of lithium aluminium hydride are added and,the reaction medium is stirred for 1 hour. The reaction is hydrolysed by sequential addition of 130 L of water, 130 L of 15% sodium hydroxide solution.and 400 L of water. The reaction medium is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is dissolved in 30 mL of dichloromethane, and 2 g (23 mmol) of manganese dioxide are added. The medium is refluxed for 5 hours, and filtered through Celite. A
yellow oil is obtained (m = 780 mg; yield = 85%).

f. 1 -(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)prop -2 -yn-1-o1 780 mg (2.2 mmol) of 6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarbaldehyde are dissolved in 50 mL of THF, and the reaction medium is cooled to 0 C.
5.7 mL (2.8 mmol) of 0.5 M ethynylmagnesium bromide solution are added slowly. The medium is stirred at 0 C
for 2 hours and the reaction is then treated with a saturated ammonium chloride solution. The residue obtained is purified by chromatography on a column of silica (eluent: 9 heptane / 1 ethyl acetate). A yellow oil is obtained (m = 740 mg; yield = 89%).

g. 4-(3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-hydroxy-1-propynyl]benzoic acid 740 mg (1.9 mmol) of 1-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)prop-2-yn-l-ol are dissolved in 15 mL of triethylamine and 1 mL of dimethylformamide. 390 mg (1.6 mmol) of 4-iodobenzoic acid and 30 mg (0.15 mmol) of copper iodide are added.

The medium is degassed with a flow of nitrogen, and-56 mg (0.08_ mmol) of bis(triphenylphosphine)dichloropalladium are then added. The reaction medium is stirred for 14 hours at room temperature and then treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with 1 N
hydrochloric acid solution and then dried and concentrated. The residue obtained is purified by chromatography on a column of silica (eluent: 1 heptane / 1 ethyl acetate). The solid obtained is then recrystallized from a heptane / ether mixture. A white solid is obtained (m = 270 mg; yield = 35%;

m.p. = 170 C).

''H NMR/CDC13+DMSO 1.38 (s, 9H); 2.29 (s, 3H); 4.37 (s, 2H); 5.50 (s, 1H); 5.57 (s, 1H); 7.03 (d, J=6Hz, 2H); 7.11 (d, J=8Hz, 2H); 7.17-7.20 (m, 2H);
7.36 (s, 1H) ; 7.42-7.5,(m, 5H) ; 7.51 (s, 1H) ; 7.9 (d, J=8Hz, 2H).

EXAMPLE 2 - 4- [ (E) -3- (6-Benzyloxy-5-tert-butyl-4 ' -methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid a. 1-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)ethanone 2 g (5.1 mmol) of methyl 6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarboxylate (Example 1,d) are dissolved in 30 mL of THF, 15 mL of methanol and 2 mL

of water. 320 mg (7.7 mmol) of lithium hydroxide hydrate are added and the reaction medium is=refluxed for 5 hours and then cooled. The medium is neutralized with a 1 N hydrochloric acid solution and the medium is then extracted with ethyl ether. A white powder is obtained (m.p. = 196 C), which is dissolved in 10 mL of ethyl ether and 5 mL of THF. The medium is cooled to -78 C, and 11 mL (11 mmol)'of 1 N methyllithium solution are then added dropwise. The medium is stirred at this temperature for 3 hours and is then treated with 5 mL of trimethylsilyl chloride. The medium is hydrolysed with a saturated ammonium chloride solution and then extracted with ethyl ether. The residue obtained is purified by chromatography (eluent: 9 heptane / 1 ethyl acetate). A yellow crystalline solid is obtained (m = 1.1 g; yield = 60%; m.p. = 104 C).

b. 4-((E)-3-(6-Benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 970 mg (2.6 mmol) of 1-(6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylyl)ethanone are dissolved in 40 mL of methanol. 350 mg (2.3 mmol) of 4-carboxybenzaldehyde are added, followed by 1.23 mL
(10 mmol) of 47% KOH. The reaction medium is stirred for 36 hours and then acidified with concentrated hydrochloric acid. The medium is extracted with ethyl acetate, and the residue obtained is purified.by chromatography on a column of silica. The solid obtained is recrystallized from an ethyl ether /

heptane mixture. A yellow powder is obtained (m =
.500 mg; yield= 38%; m.p. = 208 C).

1H NMR/CDC13 1.50 (s, 9H); 2.42 (s, 3H); 4.55 (s, 2H);
7.13-7.25 (m, 2H); 7.28-7.30 (m, 5H).; 7.56 (d, J=8.4Hz, 2H); 7.66 (d, J=16Hz, 1H); 7.75 (d, J=8Hz, 2H); 7.85-7.90 (m, 2H) 8.10 (s, 1H); 8.17 (d, J=8Hz, 2H).

EXAMPLE 3 - 4-[(E)-3-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-oxopropenyl] benzoic acid a. Methyl 5-tert-butyl-6-hydroxy-4'-methyl-3-biphenyl carboxyl ate 5.4 g (14 mmol) of methyl 6-benzyloxy-5-tert-butyl-4'-methyl-3-biphenylcarboxylate (Example 1, d) are dissolved in 100 mL of acetonitrile. 6 mL (41 mmol) of trimethylsilyl iodide are added and the mixture is heated at 50 C for 24 hours. After extraction, the residue obtained is subjected to esterification conditions similar to those of Example 1 b, and the residue obtained is purified by chromatography. A white solid is obtained (m = 1.6 g, yield = 36%;

m.p. = 105 C).

b. Methyl 5-tert-butyl-6-isobutoxy-4',-methyl-3-biphenylcarboxylate in a manner similar to that of Example 1 c, by reacting 1.57 g (5.3 mmol) of methyl 5-tert-butyl-6-hydroxy-4'-methyl-3-biphenylcarboxylate with 1.14 mL
(10.5 mmol) of isobutyl bromide. A yellow oil is obtained (m = 1.8 g; yield = 95%).

c. I-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-5 ' biphenylyl) ethanone In a similar manner to that of Example 2 a, by reacting 1.8 g (5.1 mmol) of methyl 5-tert-butyl-6-isobutoxy-4'-methyl-3-biphenylcarboxylate with 330 mg (7.9 mmol) of lithium hydroxide hydrate, followed by 10 reacting the acid obtained (1.2 g; 3.8 mmol) with 11 mL
(11 mmol) of 1 M methyllithium solution. A colourless oil is obtained (m = 1 g; yield = 54%).

d. 4- [ (E) -3- (5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid 15 In a similar manner to that of Example 2 b, by reacting 1 g (2.9 mmol) of 1-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)ethanone with 400 mg (2.6 mmol) of 4-carboxybenzaldehyde. A yellow solid is obtained (m = 700 mg; yield = 50%; m.p. = 243 C).

20 'H NMR/CDC13 0.78 (d, J=8Hz, 6H); 1.51 (s, 9 H); 1.75-1.9 (m, 1H); 2.44 (s, 3H); 3.27 (d, J=4Hz, 2H); 7.27 (d, J=8Hz, 2H); 7.46 (d, J=8Hz, 2H); 7.65 (d, J=16Hz, 1H); 7.74 (d, J=BHz, 2H); 7.82-7.84 (m, 2H); 8.06 (s, 1H); 8.16 (d, J=8Hz, 2H).

EXAMPLE 4 - 4-((E)-3-(5-tert-Butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-hydroxypropenyl] benzoic acid 440 mg (0.9 mmol) of 4-[(E)-3-(5-tert-butyl-6-isobutoxy-4'-methyl-3-biphenylyl)-3-oxopropenyl]benzoic acid are dissolved in 50 mL of methanol. 450 mg (1..2 mmol) of cerium chloride heptahydrate are added, and the medium is stirred for 30 minutes. 70 mg (1.9 mmol) of sodium borohydride are then added, and the reaction medium is stirred for 15 minutes until completely decolorized, and then treated with a saturated ammonium chloride solution.
The, residue obtained after extraction with ethyl acetate is purified by chromatography (eluent: 1 heptane / 1 ethyl acetate). A white crystalline solid is obtained after recrystallization from a heptane /
ethyl acetate mixture (m =,180 mg; yield = 42%; m.p. _ 175 C).

1H NMR/CDC13+DMSO; 0.71 (d, J=8Hz, 6H) ; 1.42 (s, 9 H);
1.7 (m, 1H); 2.39 (s, 3H); 3.15 (d, J=8Hz, 2H); 5.34 (d, J=6Hz, 1H); 6.53 (d, J=8Hz, 1H); 6.73 (d, J=12.4Hz, 1H); 7.16-7.18 (m, 2H); 7.33 (s, 1H);
7.38-7.43'(m, 4H); 7.97 (d, J=8Hz, 2H).

EXAMPLE 5 - 4-(3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)-l-propynyl]benzoic acid a. 3-Formyl-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-l-naphthyl 1,1,1-trifluoromethanesulphonate 6 g (26 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde (Example 16 a) are dissolved in 150 mL of dichloromethane. 6.8 mL (39 mmol) of triethylamine are added, followed by dropwise addition of a solution of 10.4 g (29.mmol) of 1,1,1-trifluoro-N-phenyl-N-trifluotomethanesulphonylmethanesulphonamide in 50 mL of dichloromethane. Acatalytic amount of dimethylaminopyridine is added and the reaction medium is stirred for 48 hours at room temperature. After the usual treatment with a saturated ammonium chloride solution, the residue obtained is purified by chromatography (eluent: 5 ethyl acetate / 95 heptane).
A white crystalline solid is obtained (m = 8.9 g;
yield = 94%; m.p. = 700C).

b. 5, 5, 8, 8-Tetramethyl-4-p-tolyl-5, 6, 7, 8-tetrahydro-2-naphthal enecarbaldehyde 1.4 g (3.8 mmol) of 3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-l-naphthyl 1,1,1-trifluoromethanesulphonate are dissolved in 50 mL of DME, followed by 625 mg (4.6 mmol) of p-tolylboronic acid. 485 mg (11.4 mmol) of lithium chloride and 4.6 mL
(9.2 mmol) of 2 M potassium carbonate solution are added to the reaction medium, which-is then degassed with a flow of nitrogen and then heated to 90 C. 220 mg of tetrakis(triphenylphosphine)palladium are added and the reaction medium is stirred at reflux for 20 hours, then hydrolysed and extracted with ethyl acetate. The .residue obtained is purified by chromatography, to give an orange-coloured oil (m = 980'mg; yield = 85%).

c. 1- (5, 5, 8, 8-Tetramethyl-4-p-tolyl-5, 6, 7, 8-tetrahydro-2-naphthyl)prop-2-yn-1-o1 in a similar manner to that of Example 1 f, by reacting 950 mg (3.1 mmol) of 5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 4.5 mL (4.5 mmol) of 1 N ethynylmagnesium bromide solution. A dolourless oil is obtained (m = 1 g;

yield = 980).

d. 4-[3-Hydroxy-3- (5, 5, 8, 8-tetramethy1-4-p-to1y1-5, 6, 7, 8-tetrahydro-2-naphthyl) -1-propynyl]benzoic acid In a similar manner to that of Example 1 g, by reacting 950 mg (2.9 mmol) of 1-(5,5,8,8-tetramethyl-4-p-.tolyl-5,6,7,8-tetrahydro-2-naphthyl)prop-2-yn-1-ol with 595 mg (2.4 mmol) of 4-iodobenzoic acid in the presence of 47 mg of copper iodide and 54 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals.

(m = 1 g; yield = 81%; m.p. = 207 C).

1H NMR (DMSO) : 1.07 (s, 6H); 1.38 (s, 6H) ; 1.59-1.61 (m, 2H); 1.73-1.76 (m, 2H); 2.41 (s, 3H); 5.62 (d, J =
5.1 Hz, 1H); 6.18 (d, J =5.1 Hz, 1H); 6.91 (s, 1H);

7.18-7.24 (m, 4H); 7.61 (m, 1H); 7.56 (d, J = 8.3 Hz, 2H); 7.98 (d, J = 8.2 Hz, 2H); 13.4 (bs, 1H).

EXAMPLE 6 - 4-{3-[4-(4-tert-Butylphenyl)-5,5,8,8 tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-l-propynyl}benzoic acid a. 4- (4-tert-Butylphenyl) -5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthal.enecarbaldehyde In a manner similar to that of Example 21 b, by reacting 5 g (14 mmol) of 3-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-l-naphthyl 1, 1, 1-trifluoromethanesulphonate (Example 21 a) with 2.85 g (16 mmol) of 4-tert-butylphenylboronic acid, in the presence of 1.17 g (28 mmol) of lithium chloride, 16 mL

(32 mmol) of 2 M potassium carbonate solution and 800 mg of tetrakis(triphenylphosphine)palladium. The product is obtained in the form of white crystals (m = 3.1 g; yield = 65%, m.p. = 129 C).

b. 1- (4- (4-tert-Butylphenyl) -5, 5, 8, 8-tetramethyl-5,6, 7, 8-tetrahydro-2-naphthyl]prop-2-yn-l-ol In a manner similar to that of Example 1 f, by reacting 350 mg (1 mmol) of 4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 2.6 mL (1.3 mmol) of 0.5 N

ethynylmagnesium bromide solution. White crystals are obtained (m = 300 mg; yield = 800).

c. 4- f3-Hydroxy-3- (5, 5, 8, 8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)prop-1-ynyl]benzoic acid In a similar manner to that of Example 1 g, by reacting 300 mg (0.8 mmol) of 1-[4-(4-tert-5 butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-l-ol with 166 mg (0.7 mmol) of 4 iddobenzoic acid in the presence of 7 mg of copper iodide and 12 mg of bis(triphenylphosphine)dichloropalladium. The desired 10 product is obtained in the form of white crystals (m = 280 mg; yield = 72%; m.p. ='180 C).

1H NMR (DMSO) 1.02 (s, 6H); 1.33 (m, 15H); 1.55 (m, 2H);
1.68 (m, 2H); 5.55 (s, 1H); 6.10 (s, 1H); 6.85 (d, 1H, 4Hz); 7.18 (d, 2H, 1.6Hz); 7.38 (d, 2H, 8.4Hz); 7.50 15 (d, 2H, 8Hz); 7.54 (d, 1H, 2Hz); 7.91 {d, 2H, 8Hz).
EXAMPLE 7 - 4-(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid 20 a. 3-Acetyl-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-l-naphthyl 1,1,1-trifluoromethanesulphonate In a manner similar to that of Example 21a, by reacting 8.2 g (33 mmol) of 1-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethanone 25 (Example 20 a) with 13 g (36 mmol) of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulphonylmethanesulphonamide and 8.7 mL (50 mmol) of diisopropylethylamine. A white solid is obtained (m = 11.2 g; yield = 90%)..

b. 1- (5, 5, 8, 8-Tetramethyl-4-p-to1y1-5, 6, 7, 8-tetrahydro-2-naphthyl)ethanone In a manner similar to that of Example 21 b, by reacting 1.4 g (3.7 mmol) of 3-acetyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-l-naphthyl.1,1,1-trifluoromethanesulphonate with 625 mg (4.6 mm ol) of p-tolylboronic acid, 485 mg (11.4 mmol) of lithium chloride, 4.6 mL (9..2.mmol) of a 2 M potassium carbonate solution and 220 mg of tetrakis(triphenylphosphine)palladium. The desired product is obtained in the form of white crystals (m = 830 mg; yield = 70%; m.p. = 102 C).

c. 4- [ (E) -3-Oxo- (5, 5, 8, 8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyllbenzoic acid In a similar manner to that of Example 2b, by reacting 770 mg (2.4 mmol) of 1-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)ethanone with 320 mg (2.2 mmol) of 4-carboxybenzaldehyde and 1.2 mL
(10 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m = 780 mg; yield = 72%;
m.p. = 242 C).

1H NMR (CDC13) : 1.10 (s, 6H) ; 1.42 (s, 6H) ; 1.61-1.64 (m, 2H); 1.74-1.77 (m, 2H); 2.43 (s, 3H); 7.20-7.22 (m, 4H); 7.43 (s, 1H); 7.54 (d, j =,15.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H); 7.80 (d, J = 15.7 Hz, 1H); 8.07 (s, 1H); 8.11 (d, J = 8.4 Hz, 2H).

EXAMPLE 8 - 4-{(E)-3-[4-(4-tert-Butylphenyl)-=5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid a. 1-j4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthyl]ethanone In a manner similar to that of Example .2 b, by reacting 1.3 g (3.4 mmol) of 3-acetyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-l-naphthyl 1,1,1-trifluoromethanesulphonate with 600 mg (4.4 mmol) of 4-tert-butylphenylboronic acid, 450 mg (10.8 mmol) of lithium chloride, 4.6 mL (9.2 mmol) of 2 M potassium carbonate solution and 220 mg of tetrakis(triphenylphosphine)palladium. The desired product is obtained in the form of white crystals (m = 812 mg; yield = 66%; m.p. = 134 C).

b. 4-{ (E) -3- f4- (4-tert-Butylphenyl) -5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid In a manner similar to that of Example 2b, by reacting 710 mg (2.0 mmol) of 1-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]ethanone with 260 mg (1.8 mmol) of 4-carboxybenzaldehyde and 1.0 mL (8 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m = 590 mg; yield = 61%; m.p. = 241 C).
1H NMR (CDC13) : 1.02 (s, 6H) ; 1.32 (s, 9H) ; .1.37 (s, 6H); 1.54-1.57 (m, 2H); 1.68-1.71 (m, 2H); 7.15-7.17 (m, 2H); 7.31 (d, J = 8.3 Hz, 1H); 7.38 (s, 1H);
7.48 (d, J = 15.7 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H);
7.73 (d, J =-15.7 Hz, 1H); 8.00 (s, 1H); 8.04 (d, J = 8.5 Hz, 2H).

EXAMPLE 9 - 4-((E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid In a manner similar to that of Example 4 a, by reacting 400 mg (0.88 mmol) of 4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyllbenzoic acid (Example 23) with 428 mg of cerium chloride heptahydrate and 40 mg of sodium borohydride. The desired product is obtained in the form of a white solid (m,= 200 mg; yield = 50%;

m.p. = 179 C).

1H NMR (CDC13): 1.05 (s, 6H); 1.36 (s, 6H); 1.56-1.58 (m, 2H); 1.70-1.72 (m, 2H)-; 2.38 (s, 3H); 5.26 (d, J = 7Hz, 1H); 6'.51 (dd, J1= 15.8Hz, J2 = 6Hz, 1H); 6.72 (d, J = 15.8 Hz, 1H); 6.82 (s, 1H); 7.10-7.15 (m, 4H);
7.43 (s, 1H); 7.43-7.59 (m, 3H); 8.25 (bs, 2H).

The activation of receptors with an agonist (activator) in HeLa cells leads to the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. The activation of the receptors may thus be measured by quantifying the luminescence produced after incubating the cells in the presence of a reference agonist. The inhibitory products displace the agonist from its site, thus preventing activation of the receptor. The activity is measured by.quantifying the reduction in light produced. This measurement makes it possible to determine the inhibitory activity of the compounds according to the invention.

Determination of the Kdapp:

In this study, a constant is determined which represents the affinity of the molecule for the receptor. Since this value can fluctuate depending on the basal activity and the expression of the receptor, it is referred to as the IKd apparent (KdApp).

To determine this constant, "crossed curves"
of the test product against a reference agonist, 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid, are performed in 96-well plates. The test product is used at 10 concentrations and the reference agonist at 7 concentrations. In each well, the cells are in contact with a concentration of the test product and a concentration of the reference agonist, 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-5 naphthyl)propenyl]benzoic acid. Measurements are also taken for the total agonist (4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid) and inverse agonist, 4-{(E)-3-[ 4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-10 oxopropenyl}benzoic acid, controls.

These crossed curves make it possible to determine the AC50 values (concentration at which 50%
activation is observed)'-for the reference ligand at various concentrations of test product. These AC50 15 values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation ("quantition in receptor pharmacology" Terry P.Kenakin, Receptors and Channels, 2001,7,371-385).

In the case of an antagonist, an IC50 value 20 (concentration that inhibits 50% of the activity) is calculated by plotting the curve of the product at the concentration of the reference ligand that gives 80%
activation:.

The HeLa cell lines used are stable 25 transfectants containing the plasmids ERE-(3Glob-Luc-SV-Neo (reporter gene) and RAR ((X, (3, 'y) ER-DBD-puro. These cells are inoculated into 96-well plates at a rate of 000 cells per well in 100 l of. DMEM medium without phenol red, and supplemented with 10% defatted calf serum. The plates are then incubated at 37 C and 7% CO2 for 4 hours.

5 The various dilutions of the test products, of the reference ligand (4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid), of the 100% control (100 nM 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)propenyllbenzoic acid) 10 and of the 0% control (500 nM 4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid) are added at a rate of 5 gl per well. The plates are then incubated for 18 hours at 37 C and 7% C02-The culture medium is removed by turning over and 100 gl of a 1:1 PBS/luciferine mixture is added to each well. After 5 minutes, the plates are read using the luminescence detector.

RAR ALPHA RAR BETA PAR GAMMA
IC50 Kd app IC50 Kd app IC50 Kd app (rim) (rim) (nI) (nM) (rim) (rim) Ex9 437.5 250 800 500 75 30 Ex8 3.5 2 6.4 4 0.625 0.25 Ex5 7000 4000 96 60 37.5 15 Ex7 1.75 1 0.4 0.25 2.5 1 The results obtained with the compounds according to the invention clearly show Kd app values <_ 100 nM and an IC50 value <_ 100 nM for at least one of the receptor subtypes, this clearly demonstrating a reduction in the signal, and in the luminescence in the presence of the reference agonist. The compounds according to the invention are thus clearly inhibitors of retinoic acid receptors (RAR).

EXAMPLE 11: FORMULATION EXAMPLES

This example illustrates various concrete formulations based on the compounds according to the invention.

A - ENTERAL ROUTE

(a) 0.2 g tablet - Compound of Example 6 0.001 g - Starch 0.114 g - Dicalcium phosphate 0.020 g - Silica 0.020 g - Lactose 0.030 g Talc 0.010 g - Magnesium stearate 0.005 g (b) Drinkable suspension in 5 ml ampules - Compound of Example 7 0.001 g - Glycerol 0.500 g - 70% sorbitol 0.500. g - Sodium saccharinate 0.010 g - Methyl para-hydroxybenzoate 0.040 g - Flavouring qs - Purified water qs 5 ml (c) 0.8 g tablet - Compound of Example 9 0.500 g - Pregelatinized starch 0.100 g - Microcrystalline cellulose 0.115 g - Lactose 0.075 g - Magnesium stearate 0.010 g (d) Drinkable suspension in 10 ml ampules - Compound of Example 2 0.200 g - Glycerol 1.000 g 70% sorbitol 1.000 g - Sodium saccharinate 0.010 g.
Methyl para-hydroxybenzoate 0.080.g Flavouring qs - Purified water qs 10 ml B - PARENTERAL ROUTE

(a) Composition Compound of Example 3 0.002 g - Ethyl oleate qs 10 g (b) Composition - Compound of Example 1 0.05%.
- Polyethylene glycol 20%
0.9% NaCl solution qs 100 (c) Composition - Compound of Example 3 2.5%
- Polyethylene glycol 400 20%

- 0.9% NaCl solution qs 100 (d) Injectable cyclodextrin composition - Compound of Example 3 0.1 mg - (3-Cyclodextrin 0.10 g - Water for injection qs 10.00 g C - TOPICAL ROUTE

(a) Ointment - Compound of Example 2 0.020 g - Isopropyl myristate 81.700 g - Liquid petroleum jelly fluid 9.100 g Silica ("Aerosil 200*" sold by Degussa) 9.180 g (b) Ointment * trademark Compound of Example 5 0.300 g - White petroleum jelly codex qs 100 g (c) Nonionic water-in-oil cream - Compound of Example 4 0.100 g Mixture of emulsifying lanolin alcohols,. waxes and oils ("Anhydrous Eucerin" sold by BDF) 39.900 g 10 - Methyl para-hydroxybenzoate 0.075 g - Propyl para-hydroxybenzoate 0.075 g - Sterile demineralized water qs 100 g (d) Lotion - Compound of Example 9 0.100 g - Polyethylene glycol (PEG 400) 69.900 g - 95% ethanol 30.000 g (e) Hydrophobic ointment Compound of Example 2 0.300 g - Isopropyl myristate 36.400 g - Silicone oil ("Rhodorsil 47 V 300"

sold by Rhone-Poulenc) 36.400 g - Beeswax 13.600 g - Silicone oil ("Abil 300 000 cst*" sold by Goldschmidt) qs 100 g (f) Nonionic oil-in-water cream * trademark - Compound of Example 6 1.000 g Cetyl alcohol 4.000 g - G1yc.eryl monostearate 2.500 g - PEG-50 stearate 2.500 g - Karite butter 9.200 g - Propylene glycol 2.000 g - Methyl Para-hydroxybenzoate 0.075 g - Propyl para-hydroxybenzoate 0.075 g - Sterile demineralized water qs 100 g

Claims (17)

WHAT IS CLAIMED IS:
1. A biaryl compound having the structural formula:
wherein:
R10 is a hydrogen atom or an -OH radical;

R11 is a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms or R10 and R11 together represent a CO radical;

R13 is a hydroxyl, alkoxy, monoalkylamino or dialkylamino group;
R14 is a hydrogen atom, a hydroxyl group or amino group; and the para-position of the benzene ring bonded to the 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene is optionally substituted with a linear or branched alkyl radical having from 1 to 6 carbon atoms, an alkoxy radical, a monoalkylamino radical, a dialkylamino radical or a halogen atom, a salt or an optical or geometrical isomer thereof.
2. The biaryl compound as defined by claim 1, wherein the bond represented by the dashed line is a double bond.
3. The biaryl compound as defined by claim 1, wherein the bond represented by the dashed line is a triple bond.
4. The biaryl compound as defined by claim 1, wherein the para-position of the benzene ring bonded to the 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene is optionally substituted with an alkyl, alkyl amino or alkyloxy group.
5. A salt of the biaryl compound as defined by claim 1.
6. An alkali or alkaline-earth or zinc or organic amine salt of the biaryl compound as defined by claim 1.
7. The biaryl compound as defined by claim 1, further containing at least one alkyl radical selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl radicals.
8. The biaryl compound as defined by claim 1, containing at least one fluorine, chlorine or bromine atom.
9. The biaryl compound as defined by claim 1, containing at least one alkoxy radical selected from the group consisting of methoxy, ethoxy, propyloxy, isopropoxy, butoxy, tert-butoxy, pentoxy and hexyloxy radicals.
10. The biaryl compound as defined by claim 1, selected from the group consisting of:
4-[3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphth-yl)-propynyl]benzoic acid, 4-{3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}benzoic acid, 4-{(E)-3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid, 4-[(E)-3-Oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid, 4-[(E)-3-Hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid;
4-{(E)-3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid, 4-{3-[4-(4-tert-Butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}-2-hydroxybenzoic acid, 2-Hydroxy-4-[(E)-3-hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-naphthyl)propenyl]benzoic acid, 2-Hydroxy-4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid, 2-Hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoic acid, 4-{(E)-3-[4-(4-Dimethyl aminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid, 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid, 4-{3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}benzoic acid, 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid, 4-{3-[4-(4-Dimethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid, 4-{(E)-3-[4-(4-Diethyl aminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid, 4-{3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}benzoic acid, 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid, 4-{3-[4-(4-Diethylaminophenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}benzoic acid, 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}benzoic acid, 4-{3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}benzoic acid, 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxypropenyl}-2-hydroxybenzoic acid, 4-{(E)-3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-oxopropenyl}-2-hydroxybenzoic acid, and 4-{3-[4-(4-Methoxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-3-hydroxy-1-propynyl}-2-hydroxybenzoic acid.
11. A pharmaceutical composition comprising at least one biaryl compound as defined by claim 1, a salt or an optical or geometrical isomer thereof, formulated into a physiologically acceptable medium therefor.
12. The pharmaceutical composition as defined by claim 11, said at least one biaryl compound, salt or isomer, comprising from 0.001% to 10% by weight thereof.
13. The pharmaceutical composition as defined by claim 11, said at least one biaryl compound, salt or isomer, comprising from 0.01% to 1% by weight thereof.
14. A cosmetic composition comprising at least one biaryl compound as defined by claim 1, a salt or an optical or geometrical isomer thereof, formulated into a cosmetically acceptable medium therefor.
15. The cosmetic composition as defined by claim 14, said at least one biaryl compound, or salt or isomer, comprising from 0.001% to 3% by weight thereof.
16. The pharmaceutical composition as defined by claim 11, formulated as a paste, an ointment, a cream, a milk, a pomade, a powder, an impregnated pad, a syndet, a gel, a spray, a mousse, a stick, a shampoo, microspheres, nanospheres, lipid or polymer vesicles, a controlled release patch, a syrup, tablets, capsules, granules, an emulsion, or a dragee.
17. A composition comprising a mixture of compounds of claim 1 or 10.
CA2483817A 2002-06-04 2003-05-27 Novel ligands that are inhibitors of the rar receptors, process for preparing them and use thereof in human medicine and in cosmetics Expired - Fee Related CA2483817C (en)

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